A Novel Sustained Limus Release Eluting Balloon: 2-Year Data from - - PowerPoint PPT Presentation

A Novel Sustained Limus Release Eluting Balloon: 2-Year Data from the SELUTION SFA Trial

Universitaets-Herzzentrum Freiburg Bad Krozingen, Germany Thomas Zeller, MD

Thomas Zeller

DISCLOSURE STATEMENT OF FINANCIAL INTEREST

Thomas Zeller, MD

For the 12 months preceding this presentation, I disclose the following types of financial relationships:

• Honoraria received from: Abbott Vascular, B. Braun, Biotronik,

Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Philips-Spectranetics, TriReme, Veryan, Shockwave

• Consulted for: Boston Scientific Corp., Cook Medical, Gore &

Associates, Medtronic, Spectranetics, Veryan, Intact Vascular, MedAlliance, Vesper Medical

• Common stock: QT Medical

Thomas Zeller

Drug Coated Balloon Clinical Need

▶Novel angioplasty balloon coated with an anti-restenotic drug ▶Overcoming unmet clinical need:

▶Homogenous delivery of anti-restenotic drug reduces amount of

restenosis

▶Due to absence of any stent no stent fracture or vessel injury ▶Allows original anatomy to remain intact Positive remodeling ▶“Leaving nothing behind” allowing fast ‘normalization’ of vascular

function

▶True normalization of vasomotor function, ▶Restoration of physiological responses to stress ▶NO long-term consequences related to inflammation,

accelerated atherosclerosis and thrombosis

▶No need for long term DAPT

Thomas Zeller

Ptx On Balloons: Easier, Not Better

Source: Oral presentation TCT 2016, P. Stella.

LIMUS PACLITAXEL

Mode of action Margin of safety Anti-restenosis Tissue absorption And elution Level of competition Physician perception

ATTRIBUTE

Cytotoxic 100 fold Good More difficult Very high Controversial Cytostatic 10,000 fold Optimal Easier Low Positive

Thomas Zeller

Sirolimus Coated Balloon Challenges

Tissue Binding Capacity (TBC) of labeled Dextran, Paclitaxel and Sirolimus in 0.040-mm-thick bovine internal carotid tissue segments. Source: PNAS 2004:101(25); 9463–67

PACLITAXEL SIROLIMUS

Drug Plaque Balloon Media

Intima

Adventitia

Sirolimus Paclitaxel

Dextran

►

Absorbs quickly and tends to localize in sub-intimal space and partitions significantly in adventitia

►

Absorbs slowly and spreads throughout entire artery where it dilutes down to sub-therapeutic levels

Thomas Zeller

Sirolimus-Eluting Balloon with Sustained Release

Proprietary Micro-reservoir Technology

• Micro-reservoirs combining sirolimus & biodegradable polymer
• Sirolimus - a proven safe & effective cytostatic drug
• Offering a wider therapeutic range

Micro-reservoirs: Miniature Drug-Delivery Systems

• Optimal size micro-reservoirs achieve elution kinetics similar to best in class DES
• Controlled and sustained release of sirolimus
• Providing therapeutic effect for over 60 days

Cell Adherent Technology (CAT™)

Proprietary amphiphatic lipid technology binds micro-reservoirs to balloon surface

• Contains and protects micro-reservoirs during insertion and inflation
• Facilitates higher drug transfer efficiency allowing for low drug dose on balloon surface
• Maximises drug bioavailability

*Device not approved and available for sale in the US

Thomas Zeller

SELUTION SLR™ SIROLIMUS DEB

6 262 44 21 19

59 1 0.3 35 11 3

50 100 150 200 250 300 1 hour 7 days 28 days 60 days

Tissue Drug Concentration [ug/g] Med Alliance SELUTION - RAP Bard LUTONIX - PAX Medtronic IN.PACT - PAX

Therapeutic Effect ≥ 1 µg/g

0.5

2.8 1.0 5.7 1.8 9.9 2 4 6 8 10 12 4.0x40 6.0x150 Drug Dose [mg]

Med Alliance SELUTION - 1.0 μg/mm2 Bard LUTONIX - 2.0 μg/mm2 Medtronic IN.PACT - 3.5 μg/mm2

Arterial Tissue Drug Concentration Sirolimus (RAP) versus Paclitaxel (PAX) Drug Dose per Balloon Size En Face Scanning Electron Microscope at 24 hours

SEM Courtesy of Renu Virmani

Source: Med Alliance – Pharmacokinetics Study (2014-004) – Medtronic – Presentation R.J. Melder (LINC 2012) – Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014)

Thomas Zeller

SELUTION SLR™ vs. Competition

Drug Transfer

Source: Med Alliance – Bench Test Data on File Bard-LUTONIX & Medtronic-IN.PACT – Presentation Granada at CRT 2014.

Med Alliance SELUTION Bard LUTONIX Medtronic IN.PACT Lost during procedure 36% 83% 83% Retained on balloon 25% 12% 14% Transferred to vessel (1 hr) 39% 5% 3%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

% of Total Device Drug Load

Thomas Zeller

SELUTION SLR™ COATING DURABILITY

► Coating Durability during handling and deployment

NO FLAKING

Thomas Zeller

SELUTION SFA FIM TRIAL

To assess the safety and efficacy of the SELUTION SLR DEB in treatment

• f de-novo occluded/stenotic or re-occluded/restenotic lesions of SFA

and/or PA, assessed at multiple time points clinical, angiographic and/or ultrasound assessment ▶ Prospective, controlled, multi-center, open, single-arm clinical investigation ▶ 50 patients ▶ Angiographic Late Lumen Loss (LLL) by QVA – 6M ▶ Major adverse Events (Death, Thrombosis, Amputation, CD-TLR) 6M ▶ Primary Patency – Freedom from CD-TLR and absence of Restenosis by DUS - 6, 12 and 24M ▶ Angiographic Binary Restenosis (ABR) by QVA – 6M ▶ Composite of Freedom from Amputation and Freedom from CD- TVR – 12 and 24M ▶ Change of ABI, WIQ and Qol - 6, 12 and 24M OBJECTIVES DESIGN PRIMARY ENDPOINTS SECONDARY ENDPOINTS

ClinicalTrials.gov ID: NCT02941224

Thomas Zeller

SELUTION SFA Trial Design

• SFA & Popliteal Artery (PA)
• Male or non-pregnant female

≥ 18 years of age

• De-novo or restenotic lesion(s)

with composite length ≤ 15 cm

• Target vessel reference diameter

≥ 3.0 mm and ≤ 7.0 mm

• Multiple target lesions can be treated with

maximum of 2 overlapping DCBs

• Rutherford class 2-3-4
• Known hypersensitivity or contra-indication

to aspirin, heparin or other anticoagulant / anti-platelet therapies

• Prior vascular surgery of target lesion
• Known inadequate distal outflow / significant

inflow disease

• Remaining acute or sub-acute thrombus in

target vessel

• Use of adjunctive treatment therapies (i.e.

laser, atherectomy, cryoplasty, scoring/cutting balloon, etc.)

KEY INCLUSION CRITERIA KEY EXCLUSION CRITERIA

Thomas Zeller

SELUTION SFA Trial Management

TRIAL CENTERS

• T. Zeller (PI)

Herzzentrum Bad Krozingen

• K. Brechtel

Franziskus Krankenhaus, Berlin

• T. Albrecht

Vivantes Klinikum Neukoelln, Berlin

• D. Meyer

Hubertus Krankenhaus, Berlin

• P. Gaines, M. Lichtenberg, G. Tepe

Independent CEC committee CRO CORELAB SPONSOR

Thomas Zeller

SELUTION SFA Trial Patient Flow Chart

* 10 Patient telephone contact only: TLR & Vital status

Enrollment: Oct 26th 2016 – May 23rd 2017

Non-Clinical Inclusion / Exclusion Criteria Screened N=88 Not Eligible N=35 Withdrew Consent Prior to Procedure N=1 Withdrawn by Site N=2 SELUTIONTM DCB N=50 Completed N=43 (86%) DUS Completed N=43 Angio FU Completed N=34 (68%) Bailout Stenting N=4

Withdrew N=2 Missed Visit N=5

Completed N=47* (94%) DUS completed N=37 (74%)

Missed Visit N=1

SCREENING PROCEDURE 6 M FOLLOW-UP 12 M FOLLOW-UP Completed N=42* (84%) DUS completed N=38 (76%)

Lost to FU N= 4

24 M FOLLOW-UP

Withdrew N=2

*4 Patient telephone contact only: TLR & Vital status

Thomas Zeller

SELUTION SFA Trial Baseline Characteristics

CLINICAL CHARACTERISTICS N=50 Age, Y ± SD 69.6 ± 10.4 Male, % (n) 58% (29) Previous Intervention, % (n) 30% (13) Myocardial Infarction, % (n) 6% (3) Renal Insufficiency, % (n) 22% (11) Hypertension, % (n) 80% (40) Hyperlipidemia, % (n) 90% (45) Diabetes (Type 2), % (n) 28% (14) Smoking History, % (n) 58% (29) Anticoagulation Therapy 22% (11) Angina Pectoris 14% (7) LESION CHARACTERISTICS N=50 De Novo 96% (48) Lesion Length, mm ± SD 64.30 ± 42.8 RVD, mm ± SD 5.1 ± 0.8 % Diameter Stenosis, % ± SD 90 ± 8.0 Occlusion 30% (15) Calcification None 12% (6) Mild 44% (22) Moderate 10% (5) Moderately severe 26% (13) Severe 8% (4) Target Lesion Location, % (n) SFA prox 12% (6) SFA mid 34% (17) SFA dist 54% (27) POP 1 24% (12) POP 2/POP 3/TPT 16% (8)

Thomas Zeller

SELUTION SFA Primary Endpoint

• Calcified Target Lesion (CoreLab assessed by 360 score)
• 1,5
• 1
• 0,5

0,5 1 1,5 2 2,5 3 3,5 5 10 15 20 25 30 35

LLL

0.19 mm*

LLL at 6M (N=34)

*Late Lumen Loss presented as median value

Thomas Zeller

SELUTION SFA Minimal Lumen Diameter

10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6

Cumulative density function MLD (mm)

Pre Post Follow-up

Post 3.62 ± 0.71 FU 3.24 ± 1.02 Pre 0.80 ± 0.73

Thomas Zeller

SELUTION SFA Results In Context

Trial RANGER SFA PACIFIER Tepe et al LEVANT I FemPac BIOLUX-PI

ILLUMENATE

SELUTION Therapy Ranger IN.PACT Pacific DCB not specified Lutonix Ptx coated Passeo-18 Lux Stellarex SELUTION Mean Lesion Length (mm) 6.8 7.0 5.7 8.1 5.7 6.1 7.2 6.4 Bailout Stenting (%) 21% 21% 11% 3% 9% N/A 5% 8%

0.22 0.46 0.50 0.51 0.54 0.19*

• 0.2
• 0.1

0.0 0.1 0.2 0.3 0.4 0.5 0.6

Late Lumen Loss

6% 8% 21% 13% 7% 4% 4% 2.3% 0% 5% 10% 15% 20% 25%

6M TLR

►

Results from different trials are not directly comparable. Information provided for educational purposes.

*LLL Selution presented as median value Ranger SFA – Scheinert, D. CIRSE 2016. – PACIFIER – Werk, M. et al. Circ Cardiovasc Interv. 2012; 5(6):831-840. – Tepe, G. et al. J Endovasc Ther. 2015:727-33. - LEVANT I – Scheinert, D. et al. JACC Cardiovasc Interv. 2014;7(1):10-9. - FemPac – Werk, M. et al. Circulation. 2008;118(13):1358-65 - BIOLUX PI – Scheinert, D. et al. J Endovasc Ther. 2015;22(1):14-21 - ILLUMENATE - Schroeder, H. et al Catheter Cardiovasc Intervent. 2015;86(2):278-86 - SELUTION – Zeller, T. LINC 2018

Thomas Zeller

SELUTION SFA TRIAL ANALYSIS

• 1. Inadequate Lesion Prep: Residual Stenosis >35% by CoreLab Assessment
• 2. Moderately Severe/ Severe Calcification = Calcification score 3 or 4 by 360Score = outside of Protocol

ITT: all patients enrolled in the trial, whether or not they were treated the Investigational Device PP: all patients enrolled and treated with the Investigational Device and had no bailout . Includes only patients who had a post-procedure angio residual stenosis ≤ 30%

6M 12M 24M Cumulative Clinical Events Death 0 (0%) 0 (0%) 0 (0%) Minor and Major Amputation 0 (0%) 0 (0%) 0 (0%) Primary Patency (ITT) 88.4% 75.7% 81.6% Primary Patency (PP) 95.2% 88.9% 94.4% Freedom from Index Limb Amputation and CD TVR 97.7% 87.6% 85.4% TLR (ITT) 1 (2.3%) 6 (12.5%) 6 (12.5%) TLR (PP Lesion Prep)1 1 (2.3%) 2 (4.3%) 2 (4.3%) TLR (Ca++)2 0 (0%) 1 (6.6%) 1 (7.7%)

Clinical Results at 6M, 12M and 24M

Thomas Zeller

SELUTION SFA Freedom from TLR

Kaplan Meier Estimates

10 20 30 40 50 60 70 80 90 100 100 200 300 400 500 600 700

Freedom from TLR (%) Days post-procedure

87.5 %

360

Thomas Zeller

Mortality Rates from Trials of SFA Therapy

P Schneider, LINC 2019, Oral Presentation

All-Cause Death at 2 Years

Thomas Zeller

Mortality Rates from Trials of SFA Therapy

Adapted from P Schneider, LINC 2019, Oral Presentation

DCB: All-Cause Death at 2 Years

8.1% 6.1% 7.0% 9.5% 7.6% 7.1% 6.5% 8.3% 2.9% 0.0% 0.0% 2.0% 4.0% 6.0% 8.0% 10.0%

Thomas Zeller

SELUTION SFA Trial Rutherford

Baseline, 6M, 12 M and 24M Improvement from Baseline to 24M > 2 categories in 67% of patients >1 category in 84% of patients

Thomas Zeller

SELUTION SFA Trial ABI & WIQ

Change from Baseline to 24M: p 0.0242 Change from Baseline to 12M: p < 0.0001 Change from 6M to 12M: p = 0.0125

Baseline, 6M, 12 M and 24M

Thomas Zeller

SELUTION SFA Trial Conclusions

• First demonstration of Sirolimus safety and efficacy in peripheral intervention
• Met the primary endpoint (Median LLL 0.19mm at 6M)
• Low 6 M CD TLR maintained through 24 M
• No primary TLR event after Month 11
• Clinical improvements in Rutherford classification, ABI and Walking Impairment @

6M and was further improved to 12M and maintained to 24M

• SELUTION Sirolimus DEB is safe and effective
• Based on these data, TLR with SELUTION SLR™ DEB is not impacted by Ca++
• CD TLR were associated with high residual stenosis post procedure
• Further studies are required to confirm these findings in larger patient populations
• These results support CE Mark submission of the SELUTION SLR™ 018 PTA

Thomas Zeller

FDA Granted Breakthrough Designation for BTK